Intermediates for use in the preparation of vitamin e

ABSTRACT

Novel intermediate compounds which can be used in the preparation of phytone and Vitamin E and a process for the preparation thereof. A process for the preparation of phytone and Vitamin E from these compounds is also claimed.

[0001] The present invention relates to a process for the preparation ofintermediate compounds useful in the preparation of phytone and/orVitamin E.

[0002] Vitamin E has been prepared chemically for a long time using manyvarious processes. In general, this vitamin is prepared from anintermediate compound. European Patent 0544588 discloses a process forthe production of Vitamin E through the condensation of apolyunsaturated allyl alcohol derivative. U.S. Pat. No. 3,867,408discloses the preparation of novel ketal compounds which may be used inthe preparation of phytone which in turn is an intermediate in theproduction of Vitamin E.

[0003] We have now found a new process for the preparation of certainbeta olefinic compounds which can be used to synthesise phytone and insome cases which can be used to synthesise vitamin E directly from thisintermediate.

[0004] Accordingly, the present invention provides a process for thepreparation of a compound of general formula (I)

[0005] wherein A is a C₁ to C₂₀ hydrocarbon, Y and Z independentlyrepresent a C₁ to C₂₀ hydrocarbon which may contain an oxygenatedfunctional group, and B represents OR¹ or NHR¹ where R¹ is hydrogen or aC₁ to C₆ hydrocarbon, which process comprises reacting, in the presenceof a Lewis acid catalyst, a compound of the general formula (II)

[0006] wherein Y and Z are as herein before defined with a compound ofthe general formula (III) or a compound of general formula (IV)

[0007] wherein A, B and R are as hereinbefore defined and R is hydrogenor a C₁ to C₆ hydrocarbon.

[0008] Certain compounds of general formula (I) are novel and as suchalso form another aspect of this invention.

[0009] The process of the present invention comprises the catalyticreaction between a compound of general formula (II) and a compound ofgeneral formula (III) or general formula (IV). With regard to thecompound of general formula (II), Y and Z represent a C₁ to C₂₀hydrocarbon which may contain an oxygenated functional group. Thehydrocarbon group may be linear, cyclic, aromatic or aliphatic,substituted or unsubstituted. Where Z is a hydrocarbon, the preferredhydrocarbon is a linear aliphatic hydrocarbon, especially methyl.Compounds of general formula (II) suitable for use in the process of thepresent invention include 6-methyl-6-heptene-2-one; 2-methyl-1-heptene;2,6,10,14 tetra methyl pentadec-1-ene, 6-acetoxy 2,5,7,8-tetramethyl2-[(4-methyl pent-4-ene)-1 yl]chromene and 6-acetoxy 2,5,7,8-tetramethyl2-[(4-methyl pent-4-ene)-1 yl]chromane. The particularly preferredcompounds of general formula (II) are 6-methyl-6-heptene-2-one;6-acetoxy 2,5,7,8-tetramethyl 2-[(4-methyl pent-4-ene)-1 yl]chromene andacetoxy 2,5,7,8-tetramethyl 2-[(4-methyl pent-4-ene)-1 yl]chromane.

[0010] With regard to compounds of general formula (III), A represents aC₁ to C₂₀ hydrocarbon. The hydrocarbon may be linear or cyclic,substituted or unsubstituted and may be saturated or unsaturated.Preferably, A is a linerar aliphataic hydrocarbon, especially mathyl. Brepresents OR¹ or NR¹ where R¹ is a C₁ to C₆ aliphatic linear or cyclichydrocarbon or a C₆ aromatic hydrocarbon. Compounds of general formula(III) particularly suitable for the process of the present inventioninclude 3 methyl butanal; imines of 3-methyl butanal; 3,6-dimethyloctanal; imines of 3,6-dimethyl octanal; citral and imines of citral. Byimine is meant methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, phenyl, tosyl and benzyl imines, prepared according toknown methods.

[0011] With regard to compounds of general formula (IV), A represents aC₁ to C₂₀ hydrocarbon. The hydrocarbon may be linear or cyclic,substituted or unsubstituted and may be saturated or unsaturated and Ris a C₁ to C₆ aliphatic linear or cyclic hydrocarbon or a C₆ aromatichydrocarbon. Compounds of general formula (IV) particularly suitable forthe process of the present invention include acetals of citral; acetalsof 3-methyl butanal; acetals of 3,6-dimethyl octanal, The particularlypreferred compound is 3,6-dimethyl octanal, 3-methyl butanal, and theiracetals. By acetals, it is meant methyl, ethyl, isopropyl acetals andglycol prepared according to known methods.

[0012] The mole ratio of compound of general formula (II) to compound ofgeneral formula (III or IV) is suitably from 0.2:1 to 5:1, preferablyfrom 0.5:1 to 2:1.

[0013] The process of the present invention is carried out in thepresence of a Lewis acid. Suitable Lewis acids include compounds of thegeneral formula M(L)n wherein M represents aluminium, iron, magnesium,scandium, ytterbium, zinc, titanium, silicium and bismuth; L representsa halide, CF₃SO₃, (CF₃SO₂)₂N, ClO₄ or a C₁ to C₄ alkyl, and ncorresponds to the electronic valency of M and suitably is from 1 to 4.Alternatively, the Lewis acid may be a hydride compounds having thegeneral formula A-H wherein A represents CF₃SO₃ or (CF₃SO₂)₂N.

[0014] In particular, Lewis acids according to the aforementioneddefinitions suitable for use in the process of the present inventioninclude the metal chloride, for example the chloride of aluminium, iron,bismuth, zinc, magnesium, titanium, scandium and yttrium,trifluoromethane sulphonates of scandium, ytterbium, iron and aluminium;trifluoromethane sulphonic amide or the corresponding metal salt ofscandium, ytterbium, iron and aluminium; and trifluoromethane sulphonicacid. The preferred Lewis acid is iron trichloride. The amount ofcatalyst used in the process is suitably from 0.001 to 5 molarequivalents, preferably from 0.02 to 2.5 molar equivalents.

[0015] The process of the present invention may be carried out in thepresence of a base. Suitable bases may be chosen from aromatic amines,for example pyridine and 2,6, dimethyl pyridine; or aliphatic amines,especially tertiary amines, for example triethyl amine and di-isopropylethyl amine; or an inorganic carbonate, especially a carbonate of GroupI or Group II of the Periodic Table, for example carbonates of sodium,potassium, calcium and magnesium. The preferred base is pyridine. Theamount of base used in the process may be from 0 to 1 molar equivalent,preferably from 0.1 to 0.5 molar equivalent.

[0016] The reaction may be carried out in the presence of an organicsolvent. Suitable solvents include chlorinated solvents such asdichloromethane, chloroform or chlorobenzene; aromatic solvents, forexample toluen eand xylene; ether such as tetrahydrofuran, diethyl etherand isopropyl ether; nitrile solvents such as acetonitrile,proponitrile, and benzonitrile and nitro solvents such as nitromethaneand nitroethane. The amount of solvent present in the reaction system issuitably from 0 to 100, preferably from 2 to 10 mass equivalents.

[0017] The process may be carried out at a temperature from minus 80 toplus 150° C., preferably from minus 50 to plus 25° C. and underatmospheric or elevated pressure. Preferably, the reaction is carriedout under atmospheric pressure.

[0018] The process of the present invention may be carried out for aperiod of time from 30 minutes to 24 hours, preferably from 30 minutesto 6 hours under the aforementioned reaction conditions in order tofacilitate complete reaction of compounds of general formula (II) or(III).

[0019] Certain compounds of general formula (I) are novel and as suchform another aspect of the present invention. In particular compounds offormula V, VI, VII and VIII are novel compounds.

[0020] The compounds of general formula (I), obtained by the process ofthe present invention, are particularly suitable for use as startingmaterials in the synthesis of phytone and/or Vitamin E. Thus, accordingto another aspect of the present invention there is provided a processfor the preparation of phytone and/or Vitamin E, which comprises thehydrogenolysis of the compound of general formula (I).

[0021] In a specific embodiment of this synthesis, Vitamin E may beobtained when the starting material is selected from compound (VII) or(VIII), where Y is a hydrocarbon containing a chromane or chromenemoiety, as hereinbefore defined and phytone may be obtained when thestarting material is selected from compound (V) or (VI), where Y is alinear C₅ ketone.

[0022] The hydrogenolysis stage of the process may be carried out in thepresence of hydrogen gas and in the presence of a metal or metal salt.Suitable metals and metal salts include Raney nickel (a nickel/aluminiumalloy) optionally in the presence of iron, mangenese, cobalt, copper,zinc or chromium; zinc in the presence of acetic acid; stannouschloride; and molybdenum (III) salts. The reaction may also be carriedout in the pressence of palladium or platinum which may be supported onan suitable inert support such as charcoal. The hydrogenolysis ispreferably carried out in the presence of palladium on an inert supportsuch as on charcoal. The amount of metal or metal salt employed isgenerally from 0.01 to 3 molar equivalents, preferably from 0.05 to 2molar equivalents.

[0023] The reaction may be carried out in the presence of a solventwhich may be selected from an organic acid such as acetic acid; ethers;and aromatic hydrocarbons. The preferred solvents are acetic acid andtoluene. The amount of solvent is suitably between 0 and 20 weightequivalents. The reaction may also be carried out in the presence of ainorganic acid, for example HCl or sulphonic acid. The amount ofinorganic acid suitably is from 0 to 1 equivalents, preferably from 0.1to 0.5 equivalents.

[0024] The reaction temperature may be from 20° C. to 150° C.,preferably from 20° C. to 90° C. and under a pressure of 1 to 50 bars,preferably 1 to 10 bars.

[0025] The present invention will now be illustrated with reference tothe following examples:

[0026] Examples 1 to 6 are directed to the production of theintermediate compounds, Examples 7 is directed to the production of aphytone intermediate and Examples 8 is directed to the production ofVitamin E.

[0027] In the following examples Tf represents F₃CSO₂.

EXAMPLE 1

[0028] The reaction, as detailed below was carried out in the presenceof dichloromethane solvent using various Lewis acid catalysts and underconditions as indicated in Table 1

[0029] Eqimolar quantities of the two reactants were added under aninert atmosphere to the reactor containing the catalyst. The reactionwas left to proceed for two hours before adding aqueous saturated sodiumhydrogen carbonate magnesium sulphate, filtered and concentrated. Theproduct was isolated by chromatography on silica gel or filtrated incrude solution after concentration of. The resulting product wasextracted with ether, washed with water and dried using the solvent. Theresults are given in Table 1. TABLE 1 Temperature of Yield of Catalystand Amount Reaction (° C.) Product (%) 2.5 eq EtAlCl₂ −30 85 5% Tf₂NH 058 5% Al(NTf₂)₃ 0 15 idem +5% pyridine 20 50 5% Yb(NTf₂)₃ 0 5 5%Yb(NTf₂)₃ 20 70 5% Yb(OTf)₃ 20 35 5% Al(OTf)₃ 20 40 5% AlCl₃ 20 15 5%FeCl₃ 20 74 5% BiCl₃ 20 30 5% ZnCl₂ 20 5 5% TfOH 20 30 5% TiCl₄ 20 5

EXAMPLE 2

[0030] The reaction, as detailed below was carried out in the presenceof dichloromethane solvent at 0° C.

[0031] An equimolar mixture of 2,6,10,14 tetra methyl penta dec-1-ene(532 mg) and acetal (302 mg) was added under an inert atmosphere to thereactor containing 28 mg (0.049 equivalent) of (F3CSO₂)₂NH catalyst. Thereaction was carried out for 2 hours at 0° C. and then 2 hours at 20° C.prior to the addition of aqueous saturated sodium hydrogen carbonate.The resulting product was extracted with ether, washed with water anddried using magnesium sulphate, filtered and concentrated. The productwas isolated by chromatography on silica gel or filtrated in crudesolution after concentration of the solvent. A yield of 54% was obtainedafter purification.

EXAMPLE 3

[0032] The procedure of Example 1 was repeated using the reactants asdetailed in the reaction scheme below.

[0033] The reaction conditions, catalysts used and the resulting yieldsare given in Table 2 below. TABLE 2 Temperature of Yield of Catalyst andAmount Reaction (° C.) Product (%) 5% Yb(NTf₂)₃ 20 70 5% Al(NTf₂)₃ 20 605% Al(OTf)₃ 20 53 2.5 eq EtAlCl₂ −15 5

EXAMPLE 4

[0034] The procedure of Example 1 was repeated using the reactants asdetailed in the reaction scheme below.

[0035] The reaction conditions, catalysts used and the resulting yieldsare given in Table 3 below. TABLE 3 Temperature of Yield of Catalyst andAmount Reaction (° C.) Product (%) 2.5 eq EtAlCl₂ −30 50 2.5 eq AlCl₃−30 50 2.5 eq FeCl₃ −30 42 2.5 eq BiCl₃ −30 18 2.5 eq ZnCl₂ −30 38 2.5eq MgCl₂ −30 5 2.5 eq AlCl₃ + 0.5 eq pyridine −30 70 2.5 eq FeCl₃ + 0.5eq pyridine −30 80 2.5 eq BiCl₃ + 0.5 eq pyridine −30 5 2.5 eq ZnCl₂ +0.5 eq pyridine −30 21

EXAMPLE 5

[0036] The reaction, as detailed in the reaction scheme below, wascarried out in the presence of dichloromethane solvent at 0° C.

[0037] An equimolar mixture of the two reactants was added under aninert atmosphere to the reactor containing 2.5 mole equivalent ofdichloro ethyl aluminium catalyst (in a solution of 1.8 Mdichloromethane). The reaction was carried out for 2 hours at 0° C. inaqueous saturated sodium hydrogen carbonate. The resulting product wasextracted with ether, washed with water and dried using magnesiumsulphate, filtered and concentrated. The product was isolated bychromatography on silica gel or filtrated in crude solution afterconcentration of. The resulting product was extracted with ether, washedwith water and dried using the solvent. A yield of 10% was obtained.

EXAMPLE 6

[0038] The procedure of Example 1 was repeated using the reactants asdetailed in the reaction scheme below.

[0039] The reaction conditions, catalysts used and the resulting yieldsare given in Table 4 below. TABLE 4 Yield of Nature of TemperatureProduct R Group Catalyst and Amount of Reaction (° C.) (%) methyl 2.5 eqAlCl₃ −30 60 methyl 2.5 eq AlCl₃ + 0.5 eq pyridine −30 70 isopropyl 2.5eq AlCl₃ + 0.5 eq pyridine −30 40 methyl 2.5 eq FeCl₃ + 0.5 eq pyridine−30 92

EXAMPLE 7

[0040] Hydrogenolysis of the product obtained in examples 4, 5 and 6 wascarried out in the presence of a hydrogenolysis catalyst underexperimental conditions as given in Table 5 below and as detailed in thereaction scheme below.

[0041] The reactant and the catalyst were placed in an autoclave. Thesolvent was added. The autoclave was purged with argon prior to sealing.Hydrogen was then introduced into the autoclave to initiate thereaction. At the end of the reaction, the pressure was reduced toatmospheric pressure. The autoclave was then opened. The yield ofproduct is shown in Table 5. TABLE 5 H₂ Pressure Solvent Catalyst (bar)Conditions Yield of Product Acetic 7% Pd/5%-C  5  20° C., 30% phytone,70% acid 6 hours intermediate Acetic 5% Pd/10%-C 50 100° C., 30%phytone, 70% acid 2 hours intermediate Acetic 30% Pd/10%-C 15  50° C.,30% phytone, 70% acid 5 hours intermediate toluene 50% Pd/50% HCl  1 20° C., 80% phytone, 20% 2 hours intermediate

EXAMPLE 8

[0042] Preparation of Vitamin E starting from 6-methyl 6-hepten 6-2-one,according to the following scheme:

[0043] Step (a): Preparation of Alpha-Linallol

[0044] 24.7 ml of a 1.7 M solution of vinyl magnesium chloride in THF(42 mmols) was placed in a flask equipped with two necks, under argon.The solution was heated to 35° C., and 3.812 g (30 mmol) of 6-methyl6heptene-2-one was introduced drop by drop to the magnesium compoundover a period of 75 minutes. The mixture was then poured on to a mixtureof 20 g of ice, 24 ml of water and 4 ml of 37% hydrochloric acid. Theresulting organic phase was separated, dried over magnesium sulphate andconcentrated. The yield was 4.563 g (98%) and 95% purity.

[0045] Step (b): Access to the Chromane

[0046] 151 mg of trimethyl hydroquinone was dissolved, under argon, in 1ml of ethyl acetate, and the solution was heated at 75° C. 16.24 mg ofzinc chloride, 4 microliters of water, and 2 microliters of 37%hydrochloric acid were successively added. Alpha-linallol (154 mg) wasadded to the mixture in 30 mn. After 10 hours at 75° C., thealpha-linallol was consumed. 10 microlitres of 37% hydrochloric acid wasadded. Formation of the chromane was monitored on TLC plates. After 2hours at 75° C., the mixture was cooled to 25° C., diluted with ether,washed by a normal solution of sodium hydroxyde, and with water, driedover magnesium sulphate, filtered and concentrated. The crude chromane,thus obtained, was diluted in 5 ml of triethyl amine, heated to refluxduring five hours and cooled to 25° C. 204 mg of acetic anhydride wasthen added, and the mixture was kept at 25° C. 2 h under stirring. Themixture was concentrated under vacuum and the residue waschromatographed under silica gel. The desired acetylated chromane wasisolated with a 60% yield (198 mg).

[0047] Step (c) Access to the Chromene

[0048] 151 mg of trimethyl hydroquinone was dissolved under argon in 1ml of ethyl acetate, and the solution was heated at 75° C. 16.24 mg ofzinc chloride, 4 microliters of water, and 2 microliters of 37%hydrochloric acid were successively added. Alpha-linallol (154 mg) wasadded to the mixture over a period of 30 minutes. After 10 hours at 75°C., the mixture was cooled to 25° C., diluted with ether, washed by anormal solution of sodium hydroxyde, and with water, then dried overmagnesium sulphate, filtered and concentrated. The crude benzoquinoneadduct, thus obtained, was diluted in 5 ml of triethyl amine, heated toreflux during five hours and cooled to 25° C. 204 mg of acetic anhydridewere added, and the mixture was kept at 25° C. for 2 hours understirring. The mixture was concentrated under vacuum and the residue waschromatographed under silica gel. The desired acetylated chromene wasisolated with a 50% yield (162 mg).

[0049] Step (d):

[0050] 1 mmol of compound produced in step (b) and 1 mmol of dimethyloctanal dimethyl acetal were dissolved under inert atmosphere in 5 ml ofdichloromethane. The catalyst (5% molar equivalents of scandium triflateor iron trichloride or ytterbium triflate) was added. The mixture waskept under stirring during 15 hours at ambient temperature. 3 ml of asaturated aqueous solution of sodium hydrogeno carbonate was added. Theorganic phase was separated, dried over magnesium sulphate, andconcentrated in vacuo. The crude desired product was purified by columnchromatography on silica gel (eluent:pentane/diethyl ether:9/1 involume).

[0051] Step (e):

[0052] 1 mmol of compound produced in step (c) and 1 mmol of dimethyloctanal dimethyl acetal were dissolved under inert atmosphere in 5 ml ofdichloromethane. The catalyst (5% molar equivalents of scandium triflateor iron trichloride or ytterbium triflate) was added. The mixture waskept under stirring during 15 hours at ambient temperature. 3 ml of asaturated aqueous solution of sodium hydrogeno carbonate was added. Theorganic phase was separated, dried over magnesium sulfate, andconcentrated in vacuo. The crude desired product was purified by columnchromatography on silica gel (eluent:pentane/diethyl ether:9/1 involume).

[0053] Step (f):

[0054] 1 mmol of the product formed in steps (e) and (d), along with thecatalyst (palladium 5% on charcoal; 5% weight equivalents), were placedin an autoclave. Diethyl ether (5 ml) was added. The autoclave waspurged with argon prior to sealing. Hydrogen was then introduced (1 to 5bars) into the autoclave to initiate the reaction. At the end of thereaction, the pressure was reduced to atmospheric pressure. Theautoclave was then opened. Vitamin E was obtained after usual make-up ofthe mixture.

1. A process for the preparation of a compound of general formula (I)

wherein A is a C₁ to C₂₀ hydrocarbon, Y and Z independently represent aC₁ to C₂₀ hydrocarbon which may contain an oxygenated functional group,B represents OR¹ or NHR¹ where R¹ is hydrogen or a C₁ to C₆ hydrocarbon,which process comprises reacting, in the presence of a Lewis acidcatalyst, a compound of the general formula (II)

wherein Y and Z are as herein before defined with a compound of thegeneral formula (III) or a compound of general formula (IV)

wherein a, and b are as hereinbefore defined and r is hydrogen or a C₁to C₆ hydrocarbon.
 2. A process as claimed in claim 1 in which Y is a C₁to C₂₀ hydrocarbon with an oxygen group, Z is methyl, A is an aliphatichydrocarbon and R is CH₃.
 3. A process as claimed in claim 1 or claim 2in which compounds of formula (II) are 6-methyl-6-heptene-2-one;6-acetoxy 2,5,7,8-tetramethyl 2-[(4-methyl pent-4-ene)-1 yl]chromene or6-acetoxy 2,5,7,8-tetramethyl 2-[(4-methyl pent-4-ene)-1 yl]chromane. 4.A process as claimed in any one of the preceding claims in whichcompounds of formula (III) are 3 methyl butanal; imines of 3-methylbutanal; 3,6-dimethyl octanal; imines of 3,6-dimethyl octanal; citraland imines of citral
 5. A process as claimed in any one of the precedingclaims in which compounds of formula (V) are acetals of citral; acetalsof 3-methyl butanal or acetals of 3,6-dimethyl octanal,
 6. A process asclaimed in any one of the preceding claims in which the Lewis acid is ofgeneral formula M(L) where M represents aluminium, iron, magnesium,scandium, ytterium, zinc, titanium, silicium and bismuth; L represents ahalide, CF₃SO₃, (CF₃SO₂)₂N, ClO₄ or a C₁ to C₄ alkyl, and n correspondsto the electronic valency of M and suitably is from 1 to 4 or generalformula A-H wherein A represents CF₃SO₃ or (CF₃SO₂)₂N.
 7. A process asclaimed in claim 6 in which the Lewis acid is iron trichloride.
 8. Aprocess as claimed in any one of the preceding claims carried out in thepresence of a base selected from aromatic amines, aliphatic amines andcarbonate salts of Group I or II of the Periodic Table.
 9. A process asclaimed in any one of the preceding claims carried out in the presenceof an organic solvent selected from chlorinated solvents, organicsolvents, ether solvents, nitrile solvents and nitro solvents.
 10. Aprocess as claimed in any one of the preceding claims carried out at atemperature of from −80 to +150° C. and under atmospheric pressure. 11.Novel compounds characterised by the following structures


12. A process for the preparation of phytone and/or Vitamin E whichcomprises hydrogenolysis of the compound of general formula (I) asdefined in any one of claims 1 to 10
 13. A process as claimed in claim12 in which the hydrogenolysis is carried out in the presence of acatalyst which is a metal selected from palladium, platinum, nickel andzinc or a metal salt stannium chloride or molybdenum(III).
 14. A processas claimed in claim 13 in which the hydrogenolysis is carried out in thepresence of palladium on charcoal.
 15. A process for the preparation ofVitamin E as claimed in any one of claim 12 to 14 in which comprises thehydrogenolysis of novel compounds (VII) or (VIII) as defined in claim11.
 16. A process for the preparation of phytone as claimed in any oneof claims 12 to 14 which comprises hydrogenolysis of compound (V) or(VI) as defined in claim 11.